The focus of this Program Grant is metabolic regulation of fetal growth, emphasizing experiments in comparative reproductive and developmental physiology to determine pathogenesis and metabolic consequences of fetal growth restriction (FGR). FGR affects a large number of human pregnancies and is responsible for increased fetal, neonatal, and adult morbidity and mortality. Three Projects will address the following experimental aims and hypotheses: 1. in pregnant sheep, deprivation of glucose and amino acid supply to the fetus produces fetal insulin deficiency and insulin resistance, resulting in FGR and a limitation to nutrient therapy; 2. in pregnant sheep, placental insufficiency from abnormal growth and function produces severe FGR and limitation to nutrient therapy; 3. clinical studies in normal and FGR pregnancies are directed at fetal surveillance and fetal and placental amino acid metabolism using techniques comparable to those in the animal models, and also provide measures of placental and fetal responses to nutrient therapy. The animal studies are supported by the UCHSC Perinatal Research Facility. Clinical studies are conducted at the University of Milan, Italy, and in the UCHSC Obstetrics Service at University Hospital. The Program is supported by an Administrative Core, a Laboratory Core, and a Statistical Core. Understanding metabolic causes and consequences of FGR and mechanisms by which nutrient therapy affects placental and fetal metabolism and growth through integration of the basic and clinical research in the Program should lead to more rational preventative and therapeutic measures to diminish the severity of FGR and thus to improve fetal and neonatal survival and health.